2-methyl-2(beta-substituted ethyl)-1,3-cyclopentanedione derivatives



United States Patent 3,445,502 Z-METHYL-ZQB-SUBSTITUTED ETHYL)-1,3-

CYCLOPENTANEDIONE DERIVATIVES Richard E. Brown, Hanover, and Robert I. Meltzer, Rockaway, N.J., assignors to Warner-Lambert Pharmaceutical Company, Morris Plaines, N.J., a corporation of Delaware No Drawing. Original application Sept. 19, 1963, Ser. No.

310,146, now Patent No. 3,301,889. Divided and this application June 29, 1966, Ser. No. 561,368

Int. Cl. C07c 69/74, 87/34 U.S. Cl. 260-468 4 Claims This is a divisional application of our copending application Ser. No. 310,146, filed on Sept. 19, 1963, now U.S. Patent 3,301,889.

This invention relates to certain novel cyclopentanedione derivatives. More particularly, this invention relates to Z-methyl-ZQS-substitute'd ethyl)-1,3-cycl0pentanediones of the formula:

wherein X represents cyano,

in which R represents lower alkyl such as methyl, ethyl, propyl, butyl and the like, and Y can be an acid saltforming moiety such as hydrochloride, hydrobromide,

hydroiodide, hydrogen sulfate and the like, or X may be MeO The above intermediate is then cyclized by refluxing with phosphorous oxychloride to produce an 8-azasteroid of the formula:

"ice

Compounds of the above 8-azasteroid structure have interesting and valuable pharmacological activity and are useful as therapeutic agents. For example, they have been used in reversing circulatory collapse, drug induced or otherwise and for supplementing certain hormonal, such as estrone or testosterone, deficiencies.

We have found that the novel compounds of this invention may be produced by reacting 2-methyl-1,3-cyclo pentanedione or other 2-lower alkyl substituted cyclopentanedione with acrylonitrile. This reaction, as represented in the following equation, gives a compound wherein the substituent X is cyano.

This reaction is preferably carried out in the presence of a dilute base such as 0.2 N NaOH or other dilute base to give a pH range between 10 to 14 to avoid rupturing of the starting material or the final product.

The 2-cyanoethyl substituted cyclopentanedione can be treated further to give other compounds of this invention.

Thus, the corresponding Z-(B-carboxyethyl) derivative may be produced by hydrolyzing the corresponding cyano derivative in an acidic medium. The carbethoxy or carbomethoxy substituted derivatives may in turn be produced by esterification of the Z-(B-carboxyethyl) compound with a lower aliphatic alcohol such as ethanol or methanol. The esters can also be prepared directly from the cyano compound via the formation of an imino chloride and imino ether by reacting the cyano compound with dry hydrogen chloride in methanol or ethanol followed by hydrolyzing.

The following examples are included in order further to illustrate the invention. All temperatures are in degrees eentigra'de.

Example 1.--Preparation of Z-methyI-Z-(fl-cyanoethyD- 1,3-cyclopentanedione To a mixture of 160 m1. of standard 1 N NaOH solution and 352 ml. water is added 113.6 g. (1.024 mols) of 2-metl1yl-1,3-cyclopentanedione. The mixture is heated with stirring for 10 minutes on the steam bath. There is then added all at once a solution of 256 g. (5.12 mols) of freshly distilled acrylonitrile in 320 ml. of reagent grade dioxane. The clear solution is heated to reflux with stirring whereby a precipitate soon forms. The mitxure is refluxed with stirring for 25 hours, cooled and the solid polymer which forms is filtered off, washed several times with a dioxane-water mixture in the above ratio, and the combined filtrates are then acidified with 40 ml. of 4 N HCl. The solution formed is then concentrated under high vacuum to a mixture of solid and oil. This mixture is slurrie-d in ethyl acetate, and the solid is then filtered off and washed with a little ethyl acetate. The solid product separated weighs 42 g. and consists of a mixture of the starting dione and polymer. The ethyl acetate filtrate is diluted with chloroform, dried with MgSO, and concentrated to give 87 g. of oil containing a trace of solid. This oil is distilled to give g. of 2-methyl-2- (fl-cyanoethyl)-1,3-cyclopentanedione which is obtained as a pale yellow oil, B.P. .2 mm.

Example 2.-Prepa11ation of Z-methyI-Z-(B-carboxyethyl) -1,3-cyclopentanedione A solution of 128 g. of 2-methyl-2-((3-cyanoethyl)-1,3- cyclopentanedione in 600 ml. absolute methanol is saturated at 0 with dry hydrogen chloride and the solution left overnight at 010. The solution is evaporated under reduced pressure (aspirator) at 25 or lower to give a semisolid residue of formula which is dissolved in 1.2 liters of 1 N HCl. This solution is warmed for /2 hour on the steam bath. Crystallization starts on cooling. The crystalline slurry is extracted with ethyl acetate, the ethyl acetate washed twice with water, dried, and evaporated under reduced pressure to a solid residue of 2-rnethyl-2 (B-carboxyethyl)-1, 3-cyclopentane'dione. The product is recrystallized from benzene and the recrystallized product has a M.'P. 122 124".

Example 3.Preparation of Z-methyI-Z-(B- carbethoxyethyl) -1,3-cyclopentanedione Example 4.- Preparation of 2-methy1-2-( ,9- carb omethoxyethyl -l,3-cyclopentanedione In the same way as described in Example 3, 5.8 g. of 2-rnethyl-2-(B-cyanoethyl)-1,3-cyclopentanedione in 20 ml. of methanol gives Z-methyl-Z-(fi-carbomethoxyethyl)-1,3-cyclopentanedione as an otf-white oil, B.P. 101-103/10 mm.

It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing fromthe spirit of our invention.

Having described our invention, what we desired to secure by Letters Patent is:

1. A compound of the formula:

Cl) OH:

wherein X is a member of the group consisting of NE NH 0 c .Y, -0 and c OR OR; OR:

in which R; is lower alkyl and R lower alkyl and R is a member of the group consisting of hydrogen and lower alkyl, and Y is a member of the group consisting of hydrochloride, hydrobromide, hydroiodide and hydrogen sulfate.

2. 2-methyl-2-(li-carboxyethyl) 1,3 cyclopentanedione.

3. 2-methyl-2-(fl-carbethoxyethyl) 1,3 cyclopentanedione.

4. Z-methyi-Z-(fi carbomethoxyethyl) 1,3 cyclopentanedione.

References Cited UNITED STATES PATENTS 3/1966 Windholz et al. 260-3973 LORRAINE A. WEINBERGER, Primary Examiner.

P. J. KIILLOS, Assistant Examiner.

US. Cl. X.R. 260-464, 514, 566 

1. A COMPOUND OF THE FORMULA: 